Low versus standard calorie and protein feeding in ventilated adults with shock: a randomised, controlled, multicentre, open-label, parallel-group trial (NUTRIREA-3).

BACKGROUND: The optimal calorie and protein intakes at the acute phase of severe critical illness remain unknown. We hypothesised that early calorie and protein restriction improved outcomes in these patients, compared with standard calorie and protein targets. METHODS: The pragmatic, randomised, controlled, multicentre, open-label, parallel-group NUTRIREA-3 trial was performed in 61 French intensive care units (ICUs). Adults (≥18 years) receiving invasive mechanical ventilation and vasopressor support for shock were randomly assigned to early nutrition (started within 24 h after intubation) with either low or standard calorie and protein targets (6 kcal/kg per day and 0·2-0·4 g/kg per day protein vs 25 kcal/kg per day and 1·0-1·3 g/kg per day protein) during the first 7 ICU days. The two primary endpoints were time to readiness for ICU discharge and day 90 all-cause mortality. Key secondary outcomes included secondary infections, gastrointestinal events, and liver dysfunction. The trial is registered on ClinicalTrials.gov, NCT03573739, and is completed. FINDINGS: Of 3044 patients randomly assigned between July 5, 2018, and 8 Dec 8, 2020, eight withdrew consent to participation. By day 90, 628 (41·3%) of 1521 patients in the low group and 648 (42·8%) of 1515 patients in the standard group had died (absolute difference -1·5%, 95% CI -5·0 to 2·0; p=0·41). Median time to readiness for ICU discharge was 8·0 days (IQR 5·0-14·0) in the low group and 9·0 days (5·0-17·0) in the standard group (hazard ratio [HR] 1·12, 95% CI 1·02 to 1·22; p=0·015). Proportions of patients with secondary infections did not differ between the groups (HR 0·85, 0·71 to 1·01; p=0·06). The low group had lower proportions of patients with vomiting (HR 0·77, 0·67 to 0·89; p<0·001), diarrhoea (0·83, 0·73 to 0·94; p=0·004), bowel ischaemia (0·50, 0·26 to 0·95; p=0·030), and liver dysfunction (0·92, 0·86-0·99; p=0·032). INTERPRETATION: Compared with standard calorie and protein targets, early calorie and protein restriction did not decrease mortality but was associated with faster recovery and fewer complications. FUNDING: French Ministry of Health.

Impact of early low-calorie low-protein versus standard-calorie standard-protein feeding on outcomes of ventilated adults with shock: design and conduct of a randomised, controlled, multicentre, open-label, parallel-group trial (NUTRIREA-3).

INTRODUCTION: International guidelines include early nutritional support (≤48 hour after admission), 20-25 kcal/kg/day, and 1.2-2 g/kg/day protein at the acute phase of critical illness. Recent data challenge the appropriateness of providing standard amounts of calories and protein during acute critical illness. Restricting calorie and protein intakes seemed beneficial, suggesting a role for metabolic pathways such as autophagy, a potential key mechanism in safeguarding cellular integrity, notably in the muscle, during critical illness. However, the optimal calorie and protein supply at the acute phase of severe critical illness remains unknown. NUTRIREA-3 will be the first trial to compare standard calorie and protein feeding complying with guidelines to low-calorie low-protein feeding. We hypothesised that nutritional support with calorie and protein restriction during acute critical illness decreased day 90 mortality and/or dependency on intensive care unit (ICU) management in mechanically ventilated patients receiving vasoactive amine therapy for shock, compared with standard calorie and protein targets. METHODS AND ANALYSIS: NUTRIREA-3 is a randomised, controlled, multicentre, open-label trial comparing two parallel groups of patients receiving invasive mechanical ventilation and vasoactive amine therapy for shock and given early nutritional support according to one of two strategies: early calorie-protein restriction (6 kcal/kg/day-0.2-0.4 g/kg/day) or standard calorie-protein targets (25 kcal/kg/day, 1.0-1.3 g/kg/day) at the acute phase defined as the first 7 days in the ICU. We will include 3044 patients in 61 French ICUs. Two primary end-points will be evaluated: day 90 mortality and time to ICU discharge readiness. The trial will be considered positive if significant between-group differences are found for one or both alternative primary endpoints. Secondary outcomes include hospital-acquired infections and nutritional, clinical and functional outcomes. ETHICS AND DISSEMINATION: The NUTRIREA-3 study has been approved by the appropriate ethics committee. Patients are included after informed consent. Results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03573739.

High risk of pulmonary embolism in acute respiratory distress syndrome related to COVID-19: an observational controlled-cohort study.

BACKGROUND: COVID-19 may induce endovascular injury of pulmonary vessels and could be associated with increased risk of pulmonary embolism. The main objective was to compare the incidence of pulmonary embolism in patients with acute respiratory distress syndrome (ARDS) related to COVID-19 versus patients with pulmonary ARDS unrelated to COVID-19. METHODS: This is an observational controlled-cohort study performed at a single center of a university teaching hospital in France. The incidence of pulmonary embolism was prospectively assessed using computed tomography pulmonary angiography (CTPA) in patients with ARDS related to COVID-19 and compared to patients from a 3-year historical cohort of patients with pulmonary ARDS unrelated to COVID-19. In patients with ARDS related to COVID-19, CTPA was performed approximately 7 days after intubation or earlier in case of respiratory or hemodynamic worsening. RESULTS: CTPA was performed in 29 out of the 42 patients (69%) with ARDS related to COVID-19 and in 51 out of the 156 patients (33%) from the historical cohort of patients with pulmonary ARDS unrelated to COVID-19. Incidence of pulmonary embolism was 40% (17/42) in patients with ARDS related to COVID-19 and 3% (5/156) in the historical cohort (P=0.001). The proportion of patients with pulmonary embolism among all patients who had CTPA was 59% (17/29) in patients with ARDS related to COVID-19 and 10% (5/51) in the historical cohort (P=0.0001). After adjustment on the interval between ICU admission and computed tomography, COVID-19 remained independently associated with pulmonary embolism. CONCLUSIONS: Pulmonary embolism was particularly frequent in patients with ARDS related to COVID-19, thereby suggesting that CTPA should be systematically performed in these patients.

Inter-hospital transport of critically ill patients to manage the intensive care unit surge during the COVID-19 pandemic in France.

BACKGROUND: The COVID-19 pandemic led authorities to evacuate via various travel modalities critically ill ventilated patients into less crowded units. However, it is not known if interhospital transport impacts COVID-19 patient's mortality in intensive care units (ICUs). A cohort from three French University Hospitals was analysed in ICUs between 15th of March and the 15th of April 2020. Patients admitted to ICU with positive COVID-19 test and mechanically ventilated were recruited. RESULTS: Among the 133 patients included in the study, 95 (71%) were male patients and median age was 63 years old (interquartile range: 54-71). Overall ICU mortality was 11%. Mode of transport included train (48 patients), ambulance (6 patients), and plane plus helicopter (14 patients). During their ICU stay, 7 (10%) transferred patients and 8 (12%) non-transferred patients died (p = 0.71). Median SAPS II score at admission was 33 (interquartile range: 25-46) for the transferred group and 35 (27-42) for non-transferred patients (p = 0.53). SOFA score at admission was 4 (3-6) for the transferred group versus 3 (2-5) for the non-transferred group (p = 0.25). In the transferred group, median PaO2/FiO2 ratio (P/F) value in the 24 h before departure was 197 mmHg (160-250) and remained 166 mmHg (125-222) in the first 24 h post arrival (p = 0.13). During the evacuation 46 (68%) and 21 (31%) of the patients, respectively, benefited from neuromuscular blocking agents and from vasopressors. Transferred and non-transferred patients had similar rate of nosocomial infections, 37/68 (54%) versus 34/65 (52%), respectively (p = 0.80). Median length of mechanical ventilation was significantly increased in the transferred group compared to the non-transferred group, 18 days (11-24) and 14 days (8-20), respectively (p = 0.007). Finally, ICU and hospital length of stay did not differ between groups. CONCLUSIONS: In France, inter-hospital evacuation of COVID-19 ventilated ICU patients did not appear to increase mortality and therefore could be proposed to manage ICU surges in the future.

Disseminated invasive aspergillosis in patients with severe influenza infection.

A female 66 year-old patient, not immunocompromised, was admitted in ICU for severe influenza complicated by severe acute respiratory distress syndrome (ARDS) leading to extra-corporeal membrane oxygenation (ECMO). During ICU hospitalization, she developed a disseminated invasive aspergillosis with cerebral access and coronary occlusion which lead to cardiac arrest. Despite a successful revascularization procedure, the patient died of refractory shock.

Predictors of successful separation from high-flow nasal oxygen therapy in patients with acute respiratory failure: a retrospective monocenter study.

BACKGROUND: High-flow nasal oxygen therapy (HFOT) is a promising first-line therapy for acute respiratory failure. However, its weaning has never been investigated and could lead to unnecessary prolonged intensive-care unit (ICU) stay. The aim of this study is to assess predictors of successful separation from HFOT in critically ill patients. We performed a retrospective monocenter observational study over a 2-year period including all patients treated with HFOT for acute respiratory failure in the ICU. Those who died or were intubated without prior HFOT separation attempt, who were treated with non-invasive ventilation at the time of HFOT separation, or who received HFOT as a preventive treatment during the post-extubation period were excluded. RESULTS: From the 190 patients analyzed, 168 (88%) were successfully separated from HFOT at the first attempt. Patients who failed separation from HFOT at the first attempt had longer ICU length of stay than those who succeeded: 10 days (7-12) vs. 5 (4-8), p < 0.0001. Fraction of inspired oxygen (FiO2) ≤ 40% and a respiratory rate-oxygenation (ROX) index (calculated as the ratio of SpO2/FiO2 to the respiratory rate) ≥ 9.2 predicted successful separation from HFOT with sensitivity of 85% and 84%, respectively. CONCLUSIONS: FiO2 ≤ 40% and ROX index ≥ 9.2 were two predictors of successful separation from HFOT at the bedside. Prospective multicenter studies are needed to confirm these results.

Hyperoxia and hypertonic saline in patients with septic shock (HYPERS2S): a two-by-two factorial, multicentre, randomised, clinical trial.

BACKGROUND: There is insufficient research into the use of mechanical ventilation with increased inspiratory oxygen concentration (FiO2) and fluid resuscitation with hypertonic saline solution in patients with septic shock. We tested whether these interventions are associated with reduced mortality. METHODS: This two-by-two factorial, multicentre, randomised, clinical trial (HYPERS2S) recruited patients aged 18 years and older with septic shock who were on mechanical ventilation from 22 centres in France. Patients were randomly assigned 1:1:1:1 to four groups by a computer generated randomisation list stratified by site and presence or absence of acute respiratory distress syndrome by use of permuted blocks of random sizes. Patients received, in an open-labelled manner, mechanical ventilation either with FiO2 at 1·0 (hyperoxia) or FiO2 set to target an arterial haemoglobin oxygen saturation of 88-95% (normoxia) during the first 24 h; patients also received, in a double-blind manner, either 280 mL boluses of 3·0% (hypertonic) saline or 0·9% (isotonic) saline for fluid resuscitation during the first 72 h. The primary endpoint was mortality at day 28 after randomisation in the intention-to-treat population. This study was registered with ClinicalTrials.gov, number NCT01722422. FINDINGS: Between Nov 3, 2012, and June 13, 2014, 442 patients were recruited and assigned to a treatment group (normoxia [n=223] or hyperoxia [n=219]; isotonic [n=224] or hypertonic [n=218]). The trial was stopped prematurely for safety reasons. 28 day mortality was recorded for 434 patients; 93 (43%) of 217 patients had died in the hyperoxia group versus 77 (35%) of 217 patients in the normoxia group (hazard ratio [HR] 1·27, 95% CI 0·94-1·72; p=0·12). 89 (42%) of 214 patients had died in the hypertonic group versus 81 (37%) of 220 patients in the isotonic group (HR 1·19, 0·88-1·61; p=0·25). We found a significant difference in the overall incidence of serious adverse events between the hyperoxia (185 [85%]) and normoxia groups (165 [76%]; p=0·02), with a clinically relevant doubling in the hyperoxia group of the number of patients with intensive care unit-acquired weakness (24 [11%] vs 13 [6%]; p=0·06) and atelectasis (26 [12%] vs 13 [6%]; p=0·04) compared with the normoxia group. We found no statistical difference for serious adverse events between the two saline groups (p=0·23). INTERPRETATION: In patients with septic shock, setting FiO2 to 1·0 to induce arterial hyperoxia might increase the risk of mortality. Hypertonic (3%) saline did not improve survival. FUNDING: The French Ministry of Health.

Sequential application of oxygen therapy via high-flow nasal cannula and noninvasive ventilation in acute respiratory failure: an observational pilot study.

BACKGROUND: The aim of this study was to evaluate the clinical efficacy of humidified oxygen via high-flow nasal cannula (HFNC) alternating with noninvasive ventilation (NIV) in acute hypoxemic respiratory failure (AHRF). METHODS: We performed a prospective observational study in a 12-bed ICU of a university hospital. All subjects with a PaO2 /FIO2 of ≤300 mm Hg with standard mask oxygen and a breathing frequency of > 30 breaths/min or signs of respiratory distress were included and treated with HFNC first and then NIV. Ventilatory parameters, blood gases, and tolerance were recorded during 2 consecutive sessions of NIV and HFNC. Outcome was assessed after continuation of this noninvasive strategy. RESULTS: Twenty-eight subjects with AHRF were studied, including 23 (82%) with ARDS. Compared with standard oxygen therapy, PaO2 significantly increased from 83 (68-97) mm Hg to 108 (83-140) mm Hg using HFNC and to 125 (97-200) mm Hg using NIV (P<.01), whereas breathing frequency significantly decreased. HFNC was significantly better tolerated than NIV, with a lower score on the visual analog scale. The non-intubated subjects received HFNC for 75 (27-127) h and NIV for 23 (8-31) h. Intubation was required in 10 of 28 subjects (36%), including 8 of 23 subjects with ARDS (35%). After HFNC initiation, a breathing frequency of ≥30 breaths/min was an early factor associated with intubation. CONCLUSIONS: HFNC was better tolerated than NIV and allowed for significant improvement in oxygenation and tachypnea compared with standard oxygen therapy in subjects with AHRF, a large majority of whom had ARDS. Thus, HFNC may be used between NIV sessions to avoid marked impairment of oxygenation.

Incidence and impact of skin mottling over the knee and its duration on outcome in critically ill patients.

PURPOSE: Skin mottling is frequent and can be associated with an increased mortality rate in ICU patients with septic shock. Its overall incidence in ICU and its impact on outcome is unknown. We aimed to assess the incidence of skin mottling over the knee among all critically ill patients admitted in ICU and its role on their outcome. METHODS: An observational study over a 1-year period in a 15-bed medical ICU of a teaching hospital. Skin mottling over the knee was prospectively and qualitatively assessed by trained nurses. RESULTS: Incidence of skin mottling was 29% (230 of 791 patients) in overall, and 49% (32 of 65 patients) in the subset of patients admitted for septic shock. Skin mottling was present on the day on admission in 65% of patients and persisted more than 6 h in 59% of cases. In-ICU mortality was 8% in patients without mottling, 30% in patients with short skin mottling and 40% in patients with persistent skin mottling (p < 0.01 between all groups). In the overall population, skin mottling over the knee was associated with in-ICU mortality independently from SAPS II (aOR 3.29 [95% CI, 2.08-5.19], p < 0.0001). Among patients with skin mottling over the knee, persistence of skin mottling remained associated with increased in-ICU mortality independently of organ dysfunctions at the mottling onset (OR 2.77 [95% CI, 1.34-5.72], p = 0.004). CONCLUSIONS: Skin mottling is frequent in the general population of patients admitted in ICU. Occurrence and persistence of skin mottling are independently associated with in-ICU mortality.

Induced hypothermia in severe bacterial meningitis: a randomized clinical trial.

IMPORTANCE: Despite advances in care, mortality and morbidity remain high in adults with acute bacterial meningitis, particularly when due to Streptococcus pneumoniae. Induced hypothermia is beneficial in other conditions with global cerebral hypoxia. OBJECTIVE: To test the hypothesis that induced hypothermia improves outcome in patients with severe bacterial meningitis. DESIGN, SETTING, AND PATIENTS: An open-label, multicenter, randomized clinical trial in 49 intensive care units in France, February 2009-November 2011. In total, 130 patients were assessed for eligibility and 98 comatose adults (Glasgow Coma Scale [GCS] score of ≤8 for <12 hours) with community-acquired bacterial meningitis were randomized. INTERVENTIONS: Hypothermia group received a loading dose of 4°C cold saline and were cooled to 32°C to 34°C for 48 hours. The rewarming phase was passive. Controls received standard care. MAIN OUTCOMES AND MEASURES: Primary outcome measure was the Glasgow Outcome Scale score at 3 months (a score of 5 [favorable outcome] vs a score of 1-4 [unfavorable outcome]). All patients received appropriate antimicrobial therapy and vital support. Analyses were performed on an intention-to-treat basis. The data and safety monitoring board (DSMB) reviewed severe adverse events and mortality rate every 50 enrolled patients. RESULTS: After inclusion of 98 comatose patients, the trial was stopped early at the request of the DSMB because of concerns over excess mortality in the hypothermia group (25 of 49 patients [51%]) vs the control group (15 of 49 patients [31%]; relative risk [RR], 1.99; 95% CI, 1.05-3.77; P = .04). Pneumococcal meningitis was diagnosed in 77% of patients. Mean (SD) temperatures achieved 24 hours after randomization were 33.3°C (0.9°C) and 37.0°C (0.9°C) in the hypothermia and control group, respectively. At 3 months, 86% in the hypothermia group compared with 74% of controls had an unfavorable outcome (RR, 2.17; 95% CI, 0.78-6.01; P = .13). After adjustment for age, score on GCS at inclusion, and the presence of septic shock at inclusion, mortality remained higher, although not significantly, in the hypothermia group (hazard ratio, 1.76; 95% CI, 0.89-3.45; P = .10). Subgroup analysis on patients with pneumococcal meningitis showed similar results. Post hoc analysis showed a low probability to reach statistically significant difference in favor of hypothermia at the end of the 3 planned sequential analyses (probability to conclude in favor of futility, 0.977). CONCLUSIONS AND RELEVANCE: Moderate hypothermia did not improve outcome in patients with severe bacterial meningitis and may even be harmful. Careful evaluation of safety issues in future trials on hypothermia are needed and may have important implications in patients presenting with septic shock or stroke. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00774631.

Prone positioning in severe acute respiratory distress syndrome.

BACKGROUND: Previous trials involving patients with the acute respiratory distress syndrome (ARDS) have failed to show a beneficial effect of prone positioning during mechanical ventilatory support on outcomes. We evaluated the effect of early application of prone positioning on outcomes in patients with severe ARDS. METHODS: In this multicenter, prospective, randomized, controlled trial, we randomly assigned 466 patients with severe ARDS to undergo prone-positioning sessions of at least 16 hours or to be left in the supine position. Severe ARDS was defined as a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (FiO2) of less than 150 mm Hg, with an FiO2 of at least 0.6, a positive end-expiratory pressure of at least 5 cm of water, and a tidal volume close to 6 ml per kilogram of predicted body weight. The primary outcome was the proportion of patients who died from any cause within 28 days after inclusion. RESULTS: A total of 237 patients were assigned to the prone group, and 229 patients were assigned to the supine group. The 28-day mortality was 16.0% in the prone group and 32.8% in the supine group (P<0.001). The hazard ratio for death with prone positioning was 0.39 (95% confidence interval [CI], 0.25 to 0.63). Unadjusted 90-day mortality was 23.6% in the prone group versus 41.0% in the supine group (P<0.001), with a hazard ratio of 0.44 (95% CI, 0.29 to 0.67). The incidence of complications did not differ significantly between the groups, except for the incidence of cardiac arrests, which was higher in the supine group. CONCLUSIONS: In patients with severe ARDS, early application of prolonged prone-positioning sessions significantly decreased 28-day and 90-day mortality. (Funded by the Programme Hospitalier de Recherche Clinique National 2006 and 2010 of the French Ministry of Health; PROSEVA ClinicalTrials.gov number, NCT00527813.).

Intermittent pneumatic compression to prevent venous thromboembolism in patients with high risk of bleeding hospitalized in intensive care units: the CIREA1 randomized trial.

PURPOSE: Venous thromboembolism (VTE) is a frequent and serious problem in intensive care units (ICU). Anticoagulant treatments have demonstrated their efficacy in preventing VTE. However, when the bleeding risk is high, they are contraindicated, and mechanical devices are recommended. To date, mechanical prophylaxis has not been rigorously evaluated in any trials in ICU patients. METHODS: In this multicenter, open-label, randomized trial with blinded evaluation of endpoints, we randomly assigned 407 patients with a high risk of bleeding to receive intermittent pneumatic compression (IPC) associated with graduated compression stockings (GCS) or GCS alone for 6 days during their ICU stay. The primary endpoint was the occurrence of a VTE between days 1 and 6, including nonfatal symptomatic documented VTE, or death due to a pulmonary embolism, or asymptomatic deep vein thrombosis detected by ultrasonography systematically performed on day 6. RESULTS: The primary outcome was assessed in 363 patients (89.2%). By day 6, the incidence of the primary outcome was 5.6% (10 of 179 patients) in the IPC + GCS group and 9.2% (17 of 184 patients) in the GCS group (relative risk 0.60; 95% confidence interval 0.28-1.28; p = 0.19). Tolerance of IPC was poor in only 12 patients (6.0%). No intergroup difference in mortality rate was observed. CONCLUSIONS: With the limitation of a low statistical power, our results do not support the superiority of the combination of IPC + GCS compared to GCS alone to prevent VTE in ICU patients at high risk of bleeding.

Treatment of yew leaf intoxication with extracorporeal circulation.

Taxine, a yew tree toxin, is highly cardiotoxic. We report the case of a patient who developed severe cardiac failure and ventricular fibrillation after consuming yew leaves and who made a full recovery after extracorporeal life support. Yew poisoning can be added to the list of potential indications of extracorporeal life support for refractory toxic cardiogenic shock.

Disseminated varicella with multiorgan failure in an immunocompetent adult.

A case of fulminant disseminated varicella is reported in a 28-year-old immunocompetent man. He developed hepatitis, severe pneumonia, rhabdomyolysis and disseminated intravascular coagulation, followed by encephalopathy and multiorgan failure despite acyclovir therapy. He spent a total of 3.5 months in intensive care and rehabilitation units. Real-time PCR yielded a rapid diagnosis of varicella-zoster virus (VZV) infection and was used to monitor plasma viral load for 56 days. Plasma viral load peaked at 7.1 log(10)/ml on day 4 after symptom onset, then gradually declined and became undetectable after between 1 and 2 months; viral load in lung fluid followed a similar pattern. The glycoprotein E variant associated with increased VZV virulence was not detected, and the VZV thymidine kinase gene bore no major mutations associated with acyclovir resistance. This case serves as a reminder that varicella can be life-threatening in adults and that vaccination of individuals at risk remains essential.

Protected telescopic catheter also allows anaerobic bacteria isolation in patients with ventilatory-acquired pneumonia.

OBJECTIVE: To analyze the possibility of isolating anaerobic bacteria using protected telescopic catheter (PTC) in patients with ventilatory-associated pneumonia. DESIGN AND SETTING: A prospective epidemiological study in a 12-bed intensive care unit. PATIENTS: 104 patients with suspected ventilatory-associated pneumonia undergoing PTC for microbiological determination including specific methods for anaerobic bacteria identification (mean age 59.3, range 17-82; SAPS II 44.6+/-17.9). MEASUREMENTS AND RESULTS: We performed 156 PTC procedures. Of the 14 cases ventilatory-associated pneumonia occurred early in 6 and in 8 late. In 52 samples at least one bacteria was isolated (33.3%). Of the 156 samples 14 yielded with anaerobic bacteria, representing 26.9% of the positive samples and 9% of all the samples. CONCLUSION: Considering the potential pathogenic role of anaerobic bacteria in patients with ventilatory-associated pneumonia, the possibility of isolating these bacteria using PTC and taking into account its easiness and limited side effects should be underlined.